Process for preparing benzothiazepine derivatives

Abstract: Process for stereoselectivity preparing a cis-form of 5-(aminoalkylamino)-1,5-benzothiazepine derivative represented by formula (VI): is provided, said process comprising carrying out a stereoselective addition reaction of an o-(aminoalkylamino)thiophenyl derivative with a trans-substituted glycidic ester at an elevated temperature in a nonpolar solvent in the presence of a divalent or trivalent iron ion to prepare a threo-form intermediate, hydrolyzing the ester group of said intermediate, acetylating the hydroxyl group of said hydrolyzed compound, and subjecting said acetylated compound to a ring closure reaction to obtain the objective compound (VI).

Description: The invention relates to a process for preparing benzothiazepine derivatives. The following documents relate to relevant background art in connection with the present invention: 1. FR-A-2 623 192 discloses a process for preparing derivatives of 1,5-benzothiazepine of the formula: in which R 1 is a lower alkyl or lower alkoxy; R 2 is hydrogen or a lower alkanoyl; each of R 3 and R 4 is a lower alkyl; and one of R 5 and R 6 is hydrogen or a lower alkyl radical and the other is hydrogen or a pharmaceutically acceptable acid addition salt thereof, the process being characterised in that it consists in submitting a derivative of a propionic acid of formula: in which the symbols are as defined in relation to formula I or a reactive derivative thereof to an intra molecular cyclisation and if necessary to convert the resulting product to a pharmaceutically acceptable acid addition salt. 2. Chemical Abstracts, 104 (1986) 88616e discloses 1,5-benzothiazepine derivatives and their salts which are useful as vasodilators and psychotropic agents. The disclosed benzothiazepine derivatives are formed by the cyclisation of a threo compound of the disclosed formula IV. 3. Chemical Abstracts, 101 (1984) 191353d is concerned with the optical resolution of 3-(p-methoxyphenyl)-3-(phenylthio)propionic acid derivatives wherein the racemic acids were optically resolved using column chromatography using chemically modified 3-aminopropyl silica whereupon the chosen eluent gave the desired D- and L- isomers. 4. Chemical Abstracts 101 (1984) 171294g discloses optically active benzothiazepines in a process wherein the benzothiazepinones of the given formula I were prepared by cyclization of the propionic acids for formula II which were resolved using cinchonidine. 5. Chemical Abstracts 96 (1982) 34905w is concerned with the preparation of propionic acid derivatives by a series of steps which gave the propionic acid derivative of the disclosed formula I. 6. J. Chem. Soc. Perkin 1, 1984 1725-32 discloses the reaction of 3-phenylglycidic esters and particularly the stereoselective opening of the oxirane ring of trans-3-phenylglycidic esters with 2-nitrothiophenols and the effect of various catalysts thereon. The document discloses the production of threo -nitro esters which are a key intermediate for the synthesis of diltiazem. 7. J. Chem. Soc. Perkin 1, 1985 421-7 this document discloses the reaction of 3-phenylglycidic esters and more particularly stereo and regio selectivity in the oxirane ring opening of methyl trans -3-(4-methoxyphenyl)glycidate with various thiophenols and teaches the effects of various solvents and temperature. The document indicates the production of stereospecific glycidate esters which are useful in organic synthesis. Also a process for preparing 1,5-benzothiazepine derivatives, an addition reaction of o-substituted thiophenol and epoxide is known (H. Kugita, H.Inoue, S. Takeo, Chem.Pharm.Bull, 18 2028 (1970); H.Inoue, S. Takeo, H. Kugita, Yakugaku Zasshi, 93 729 (1973)). As illustrated in reaction scheme 1, an o-aminothiophenol or o-nitrothiophenol derivative is reacted with an appropriately substituted glycidic ester to obtain an addition product. A ring closure of the product is then carried out through several steps to obtain compound (VII). The present invention relates more particularly to a process for stereoselectively preparing a threo-form of a compound represented by formula (III): wherein Y represents hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, or phenyl or naphthyl which may be optionally substituted; n is an integer of 1 to 6; R 1 represents an amino group represented by the formula: -NR 1a R 1b wherein R 1a and R 1b each independently represents hydrogen, straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or phenyl or naphthyl which may be substituted, or R 1a and R 1b may form, taken together with the nitrogen to which R 1a and R 1b are attached, a cyclic amino group which may be substituted, provided that said cyclic amino group may further contain one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur in the cyclic skeleton; and R 2 represents C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, said process comprising reacting an o-(aminoalkylamino)thiophenol compound represented by formula (I): wherein Y, n and R 1 are as defined above with an ester of trans-3-(4-methoxyphenyl)glycidic acid represented by formula (II): wherein R 2 is as defined above, at an elevated temperature in a nonpolar solvent in the presence of a divalent or trivalent iron ion. Benzothiazepine derivatives can be prepared using the following reaction schemes 1 and 2: In the scheme, X represents hydrogen or oxygen; R 2 represents C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; and Y is as defined above. When an o-nitrothiophenol derivative is used as a starting compound, the nitro group needs to be reduced to an amino group after the first step of the addition reaction. Compound (VII) can be converted to compound (VI) which is the objective compound of the present invention through further several steps (Reaction scheme 2) (Japanese Patent application No. 302348/1991) (JP-A-520 1 865 which corresponds to EP-A-541,263). In the scheme, Y, n and R 1 are as defined above. The cis-1,5-benzothiazepine derivatives (VI) prepared by the process of the present invention are useful pharmaceutical compounds having a vasodilation action and a cardiac-muscle protecting action. The stereochemistry (cis/trans) of compound (VI) or (VII) obtained by the process mentioned above directly reflects the stereoselectivity (threo/erythro) of the addition reaction of a substituted thiophenol and a trans-substituted glicidic ester (II). Because a cis-form of compound (VI), which is important as a medicine, is derived from a threo-form addition product, it has been desired to establish the reaction conditions and the chemical structure of starting substituted thiophenols which give stereoselectively a threo-form addition product in its reaction with compound (II). It has been reported that o-nitrophenol derivatives stereoselectively react with compound (II) in the presence of a tin or zinc catalyst in an aprotic solvent to give a threo-form addition product (J. Med. Chem. 34 , 675 (1991)). It is also known that an o-aminothiophenol derivative gives mainly a threo-form product in an aprotic solvent, while the same derivative gives as a main product an erythro-form in a polar solvent (see the above mentioned reference). However, effect of catalysts has not been investigated. In order to obtain the intended cis-form of compound (VI) in high yield, the inventors of the present invention have established a novel synthesis route to compound (VI) and have investigated reaction conditions which maximize the stereoselectivity in the addition reaction of o-(aminoalkylamino) thiophenol derivatives (I) and trans-(4-methoxyphenyl) glycidic ester (II) which are starting compounds in the novel synthesis route. The novel synthesis route to 1,5-benzothiazepine provided by the present invention is summarized in the following Reaction scheme 3. In the scheme, Y, n, R 1 and R 2 are as defined above. Addition product (III) produced by Step (1) in the above reaction scheme 3 is converted to the intended compound (VI) through additional three steps. Since these steps proceed without racemization, the objective compound can also be obtained as an optically active compound, if an optically active compound is used as a starting compound (II). The reaction conditions of the above Step (1) which determine the stereochemistry of the intended compound (VI) have been investigated, and it has become apparent that reaction solvent, reaction temperature and catalyst remarkably influence the stereoselectivity of this reaction. Thus, the inventors have found that the reaction at an elevated temperature in the presence of an iron catalyst in a nonpolar solvent is preferable in order to produce selectively a threo-form addition product (III T ) in high yield in Step (1). The present invention provides a process for stereoselectivity preparing a cis-form of 1,5-benzothiazepine derivative represented by formula (VI): wherein Y represents hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, or phenyl or naphthyl which may be optionally substituted ; n is an integer of 1 to 6; and R 1 represents an amino group represented by the formula: -NR 1a R 1b wherein R 1a and R 1b each independently represents hydrogen, straight or branched C 1 - C 6 alkyl, C 3 - C 6 cycloalkyl phenyl or naphthyl which may be substituted, or R 1a and R 1b may form, taken together with the nitrogen to which R 1a and R 1b are attached, a cyclic amino group which may be substituted provided that said cyclic amino group may further contain one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur in the cyclic skeleton, the process comprising, (1) stereoselectively preparing a threo-form of a compound represented by formula (III). by reacting an o-(aminoalkylamino) thiophenol represented by formula (I): wherein Y, n and R 1 are as defined above, with a trans-3-(4-methoxyphenyl) glycidic ester represented by formula (II): wherein R 2 represents C 1 - C 6 alkyl or C 3 - C 6 cycloalkyl, at an elevated temperature in a nonpolar solvent in the presence of a divalent or trivalent ircn ion; (2) hydrolysing the ester group of the compound obtained in Step (1) to yield a carboxylic acid represented by formula (IV): (3) acetylating the 2-hydroxyl group of the carboxylic acid obtained in Step (2) to convert it into a 2-acetoxy compound represented by formula (V): (4) subjecting the 2-acetoxy compound obtained in Step (3) to a ring closure reaction to convert it into a 1,5-benzothiazepine derivative represented by formula (VI). In the present specification, the term halogen means fluorine, chlorine, bromine or iodine. Alkyl means straight or branched C 1 -C 6 alkyl, and includes for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 2-metylbutyl, n-hexyl, isohexyl and the like, and C 3 -C 6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term alkoxy means C 1 -C 6 alkyloxy wherein the alkyl moiety is straight or branched, and includes for example methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentoxy, i-pentoxy, neopentoxy, s-pentoxy, t-pentoxy, n-hexyloxy, neohexyloxy, i-hexyloxy, s-hexyloxy, t-hexyloxy and the like. Phenyl or naphthyl may have one or more substituents including halogen, alkyl, alkoxy, hydroxyl, amino and the like. Cyclic amino group means a 3 to 7 membered cyclic amino group which may have one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur in the cyclic skeleton and includes for example 1-piperazinyl, 1-piperidyl, 1-pyrrolidinyl, 4-morpholinyl, 4-thiomorpholinyl and the like, all of which may have one or more substituents. As substituents in said cyclic amino group, there are illustrated phenyl which may be substituted, C 1 - C 6 alkyl, phenylalkyl which may be substituted, diphenylalkyl which may be substituted, heterocyclic group, -CO-heterocyclic group and the like. The substituents on substituted phenyl, phenylalkyl and diphenylalkyl include halogen, alkyl, alkoxy, methylenedioxy and the like. Said heterocyclic group means a saturated or unsaturated 5 to 6 membered ring which have one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur and includes pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, isoxazolyl, oxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, isothiazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, furyl, thienyl and the like. Each of the steps of the process of the present invention is described below. Step (1) In order to stereoselectively obtain the threo-form intermediate (III T ) in high yield, the reaction is carried out at an elevated temperature in the presence of an iron catalyst in a nonpolar solvent. Use of the nonpolar solvent, the iron catalyst and high reaction temperature are all advantageous in the production of the threo-form ester intermediate (III T ). The term "nonpolar solvent" in this specification means aromatic hydrocarbon, alicyclic hydrocarbon, or straight or branched hydrocarbon which may be substituted. Suitable nonpolar solvents for this reaction include, for example xylene, toluene, mesitylene, cymene, decalin, chlorobenzene, tetralin and the like. Xylene is particularly preferable. The term "iron catalyst" means inorganic or organic salts or complexes containing divalent or trivalent iron ions. Suitable iron catalysts for this reaction include, for example iron (III) hydroxide oxide, iron (III) chloride, iron (II) chloride, iron sulphate, iron (II) iodide, iron sulfide, iron 4-cyclohexylbutyrate, iron (III) oxide, iron (II) oxalate, iron (III) oxalate, iron (II) fluoride, iron (III) fluoride and the like. Iron (III) hydroxide oxide is particularly preferable. Step (2) The ester groups of the threo-form ester intermediate (III T ) and the erythro-form ester intermediate (III E ) obtained in Step (1) are hydrolyzed to obtain the corresponding threo-form carboxylic acid intermediate (IV T ) and erythro-form carboxylic acid intermediate (IV E ). This reaction is achieved by stirring for several hours at a temperature between ice-cooling and room temperature in a water-containing polar solvent, for example, acetonitrile, tetrahydrofuran (THF), dioxane, ethanol, methanol, propanol, dimethylformamide (DMF), DMSO, HMPA and the like, using an equimolar amount to several-folds amount of a base such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide. The threo-form carboxylic acid intermediate (IV T ) is isolated and purified by fractionating recrystalization of the mixed carboxylic acid intermediate (IV T /IV E ) generated in this reaction. Alternatively, without isolating and purifying the threoform carboxylic acid intermediate, the mixed carboxylic acid intermediate is used as such in the next acetylation step. Then, at any one of subsequent steps the intended threo-form or cis-form compound can be isolated and purified by known techniques such as recrystallization and column chromatography. Step (3) The 2-hydroxyl groups of the threo-form carboxylic acid intermediate (IV T ) or mixed carboxylic acid intermediate (IV T / IV E ) obtained in Step (2) are acetylated to obtain the corresponding threo-form 2-acetoxy intermediate (V T ) or mixed 2-acetoxy intermediate (V T /V E ). This reaction can be achieved by conducting the acylation using acetyl chloride or acetic anhydride in an organic solvent such as dichloromethane, chloroform, ethyl acetate, acetonitrile, toluene, THF and dioxane, in the presence of an organic and inorganic base such as pyridine, dimethylaminopyridine, triethylamine, N-methyl-morpholine, NaHCO 3 and K 2 CO 3 . Step (4) The threo-form 2-acetoxy intermediate (V T ) or mixed 2-acetoxy intermediate (V T /V E ) obtained in Step (3) is subjected to a ring-closure reaction to obtain the intended 1,5-benzothiazepine derivative. The ring-closure reaction can be achieved using phosphoric anhydride, phosphorous halide, phosphorous oxyhalide, acetic anhydride or acyl halide, in an organic solvent such as dichloromethane, ethyl acetate, acetonitrile and THF, in the presence of an organic and inorganic base such as pyridine, triethylamine and NaHCO 3 . The objective compound (VI) thus obtained can be isolated and purified by recrystallization or column chromatography on silica gel. Starting compound (I) used in the above process of the present invention can be prepared by the known method (Yakugaku Zasshi 77 , 347 (1956)) (Reaction scheme 4). In the scheme, Y, n and R 1 are as defined above. As previously mentioned, the advantages of the process of the present invention for preparing a cis-form of 1,5-benzothiazepine derivatives are the threo-stereoselectivity and the high yield of the reaction of Step (1). In order to demonstrate such advantages of the present invention, the effect of solvent, reaction temperature and catalyst on the stereochemistry and yield of the ester intermediate (III) produced in Step (1) are described below. In order to examine the effects of solvent and reaction temperature on the stereochemistry and yield of the product, the yield and stereochemistry (threo/erythro ratio) of the products have been evaluated by carrying out the following reaction without catalyst in various solvents and at various temperatures (the reaction conditions other than catalyst, temperature and solvent were followed according to the description of Example 1). The results of the representative experiments are shown in Table 1. Solvent Temperature (°C) Yield(%) (III T a+III E a) Stereoselectivity III T a/III E a Xylene 50 87.1 0.01/1 Xylene 100 25.0 0.13/1 Xylene 142 61.8 3.41/1 Mesitylene 164 56.0 2.70/1 Dioxane 102 74.7 0.19/1 DMF 100 31.1 0.13/1 Ethanol 78 91.9 0.01/1 As can be seen from Table 1, this reaction proceeds in various solvents with relatively high yield. However, while the reactions in dioxane, DMF and ethanol give the threo/erythro ratio smaller than 0.2/1, the reactions carried out in a nonpolar solvent at an elevated temperature give an increased amount of the threo-form product, and particularly the reaction at reflux temperature gives the threo-form compound as the main product. Accordingly, in the process of the present invention which is directed to obtaining finally the cisform of compound (VI), this reaction is most preferably carried out in a nonpolar solvent under reflux. The Table 2 below shows the results of studies in which the effects of various metal catalysts were evaluated using the reaction condition under reflux in xylene which had showed the greatest value of threo/erythro ratio in the above experiments. Catalyst (2 mg) Yield (%) III T a+III E a Stereoselectivity III T a/III E a None 61.8 3.41/1 AlCl 3 41.3 1.44/1 BF 3 •Et 2 O 23.3 2.42/1 CoF 3 51.3 1.53/1 CuCl 2 83.7 0.34/1 Mg(OH) 2 52.8 3.05/1 MnO 2 51.0 3.69/1 NiCl 2 52.7 1.59/1 Ni(OH) 2 52.8 3.15/1 PdCl 2 95.4 0.30/1 RuCl 3 54.3 1.42/1 SnCl 2 •2H 2 O 56.5 1.10/1 SnCl 4 54.2 1.64/1 SnO 2 64.3 1.13/1 TiCl 4 22.7 1.08/1 Zn(OAc) 2 •2H 2 O 72.1 0.50/1 FeO(OH) 83.1 7.62/1 FeS 77.7 5.94/1 Fe(powder) 58.8 3.20/1 As can be seen from Table 2, the stereoselectivity of this reaction increases by using iron catalysts. Any of metal catalysts tested other than iron ion did not show significant catalytic actions or showed negative catalytic actions, i.e. the decrease of the threo/erythro ratio. The above mentioned reference (J. Med. Chem., 34 , 675-687 (1991)) has reported that, in the reaction of an o-nitrothiophenol derivative with compound (II), only the erythro-form compound is produced in ethanol/benzene in the presence of sodium hydrogen carbonate, while a threo/erythro mixture containing the threo compound as a main product is produced in toluene in the presence of zinc acetate. On the contrary, in Step (1) in the present invention, zinc acetate showed a negative catalytic action and remarkably decreased the threo/erythro ratio. Further, as can be understood from Table 2, iron powder does not show significant catalytic actions. Accordingly various iron catalysts containing divalent or trivalent iron ions can be used as the catalysts in this step. The process of the present invention is specifically illustrated by the following examples. The symbols in the chemical formulae have the following means; Me: methyl group, Ac: acetyl group, Ph: phenyl group. Examples Example 1 : Step (1)-a The reaction of Strep (1) described above was carried out using as starting compounds 5-chloro-2-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]aminobenzenethiol (Ia) and methyl (-)-trans-3-(4-methoxyphenyl)glycidate in xylene in the presence of various iron catalysts. The representative example (Run 1) is described in detail below, and the results of a series of experiments conducted according to the procedure of Run 1 except for the use of different iron catalysts are summarized in Table 3. Compound (Ia) (196 mg, 0.5 mmol), compound (II) (104 mg, 0.5 mmol) and iron (III) hydroxide oxide (2 mg) are added to dry xylene (3 ml) and refluxed for 1 hour. After cooling, the resulting reaction mixture is subjected to column chromatography on silica gel eluting with dichloromethane/ ethyl acetate (1:1). The first eluate is recrystallized from ethyl acetate/hexane to obtain methyl (-)-erythro-3-[5-chloro-2-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl)propionate (III T a) (28.9 mg) as colorless prism-shaped crystals. Yield:9.7%. Melting point:168-170°C Specific rotation: [α] D 26 =-39.2° (c=0.50,CHCl 3 ) Elemental analysis:C 31 H 38 N 3 O 5 SCl Calculated:C,62.04;H,6.38;N,7.00 Found:C,61.87;H,6.34;N,6.91 IRνmax(nujol) (cm -1 ):3386,3150,1727 NMR(CDCl 3 )δ:1.85(2H,m),2.86(12H,m),3.70(3H,S),3.76(1H,d, J=4.6),3.82(3H,S),3.87(3H,S),4.97(1H,d,d,J=8.2,4.6),5.10 (1H,m),6.49(1H,d,J=9.0),7.08(10H,m). The second eluate is converted into the oxalate which is recrystallized from ethyl acetate/ether to obtain oxalate of methyl (+)-threo-3-[5-chloro-2-[3-[4-(2-methoxyphenyl) piperazin-1-yl]propyl]aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl)propionate (III E a) (220.4 mg) as colorless prism-shaped crystals. Yield:73.4% Melting point:123-126°C Specific rotation:[α] D 23.5 =+108.4°(c=0.51,Methanol) Elemental Analysis:C 31 H 38 N 3 O 5 SCl•2C 2 O 4 H 2 Calculated:C,53.88;H,5.43;N,5.39 Found:C,53.66;H,5.40;N,5.49 IRνmax(nujol)(cm -1 ):3430,3358,1728 NMR(DMSO-d 6 )δ:1.93(2H,m),3.18(12H,m),3.45(3H,S) ,3.72 (3H,S),3.79(3H,S),4.35(1H,d,J=6.0),4.40(1H,d,J=6.0),5.55[NH , OH),6.60(1H,d,J=8.2),7.02(10H,m). Run Catalyst (2 mg) Yield(%) III T a+III E a Stereoselectivity III T a/III E a 1 FeO(OH) 83.1 7.62/1 2 FeO(OH) 81.4 7.62/1 3 FeCl 3 69.1 4.08/1 4 FeCl 2 71.6 5.10/1 5 FeI 2 66.9 4.85/1 6 FeS 77.7 5.94/1 7 Fe 2 (OH) 3 (C 10 H 17 O 2 ) 3 82.5 5.45/1 8 Fe 2 (SO 4 ) 3 71.4 4.95/1 9 Fe 2 O 3 63.8 4.46/1 Example 2 : Step (1)-b ∼ e The reaction of 5-chloro-2-N-(aminoalkyl)aminothiophenol(Ib ∼ e) and methyl (-)-trans-3-(4-methoxyphenyl)glycidate(II) was carried out according to the description in Example 1. The results are shown in Table 4. IR and NMR spectral data of compounds (III T b ∼ e) and (III E b ∼ e) produced by the above reactions are shown in Table 5. Reference Example 1 In order to further study the effects of solvent and catalyst in Step (1) in the process of the present invention, each of the reactions described in Examples 2 was carried out using a different solvent and/or catalyst and the respective yields and stereoselectivities were evaluated. The results are described in Table 6. It can be seen by comparing the results in Table 4 with those in Table 6 that even if a substituent having a different structure (R 1 -(CH 2 )n-) is located at the 5-position in the starting compound (I), the reaction condition in which the reaction mixture is refluxed in nonpolar solvent in the presence of iron catalyst is the most advantageous condition for production of the desired threo-form compound (III T ). In the following Examples 3 ∼ 7, Step (2) in the process of the present invention is illustrated. Example 3 : Step (2)-a Methyl 3-[5-chloro-2-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl) propionate(III T a+III E a, threo/erythro = 6.3/1) (131.9 g, 0.21 mol) is dissolved in acetonitrile (800 ml) and a solution of NaOH (8.4 g, 0.21 mol) in water (200 ml) is added. The resulting mixture is stirred at room temperature for 5 hours and evaporated in vacuo. The alkaline aqueous layer is neutralized to pH 4 with acetic acid and the product is crystallized by adding ethyl acetate. The precipitated crystals are filtered off, washed with water and dried to obtain crude crystals (100 g, yield = 79%, threo/erythro = 7.33/1). The resulting crystals are recrystallized from water-containing acetone to obtain the crystals (IV T a + IV E a, 85.6 g, yield = 67.8%, threo/erythro = 11.5/1 (HPLC)). This product is several times recrystallized from ethanol to obtain (+)-threo-3-[5-chloro-2-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl] aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl)propionic acid (IV T a) (purity = 100%) as colorless needle-shaped crystals. HPLC:Column, COSMOSIL 5 C18 4.6x250mm Mobile phase:acetonitrile/PICB-7 aqueous solution (50/50) Flow rate:1.0ml/min Detection:UV254nm Retention time:IV T a(6.5min),IV E a(6.2min) Melting point:108-110°C Specific rotation: [α] D 24 =+368.2° (c=1.004,Methanol) Elemental analysis:C 30 H 36 N 3 O 5 SCl·1/2H 2 O Calculated:C,60.54;H,6.26;N,7.06 Found:C,60.36;H,6.32;N,7.13 IRνmax(nujol) (cm -1 ):3332,1725 NMR(CDCl 3 )δ:2.25(2H,m),2.82-3.67(12H,m),3.79(3H,S), 3.88(3H, S),3.37(2H,m),5.10(3H),6.44(1H,d,J=8.6),6.77-7.44 (10H,m). Reference example 2 The reaction of Example 3 was carried out using the mixture containing erythro-form compound (III E a) as a main component. The results are shown below. 3-[5-Chloro-2-[3-[4-(2-methoxyphenyl)piperazin-1-yl] propyl]aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl)propionic acid (III T a + III E a, threo/erythro = 0.01/1, 391 mg, 0.65 mmol) was dissolved in THF (4 ml) and 1N NaOH (0.65 ml) was added. The resulting mixture was stirred for 3 hours and neutralized with acetic acid (0.5 ml), and water was added. The resulting mixture was extracted with ethyl acetate. The layer of ethyl acetate is dried over MgSO 4 . The solvent was distilled away to obtain (-)-erythro-3-[5-chloro-2-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl)propionic acid (IV E a) (355 mg, yield = 93.1%) as an oil. MS:m/e,586(MH+) Specific rotation: [α] D 24 =-61.3°(c=1.005 DMSO) IRνmax(CHCl 3 ) (cm -1 ):3488,3352,1690 NMR(DMSO-d 6 )δ:1.74(2H,m),2.40(4H,m),3.0(8H,m),3.35(2H), 3.69 (3H,S),3.76(3H,S),3.82(1H,d,J=2.4),4.44(1H,d,J=2.4),5.76 (NH),6.45-7.34(11H,m). Example 4 : Step (2)-b The reaction is carried out using methyl 3-[5-chloro-2-[3-(4-phenylpiperazin-1-yl)propyl]aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl)propionate (III T b + III E b, threo/erythro = 8.62/1) (2.22 mg, 4.0 mmol) in a similar manner to that described in Example 3 to obtain carboxylic acid intermediate (IV T b + IV E b, threo/erythro = 8.1/1 (NMR), 1.95 g, yield = 87.4%) in an amorphous form. Spectral data for IV T b: IRνmax(CHCl 3 )(cm -1 ) :3348,1712 NMR(CDCl 3 )δ:2.25(2H,m),2.96-3.72(12H,m),3.79(3H,S), 4.36(2H, S),5.68(3H),6.44(1H,d,J=9.0),6.76-7.44(11H,m). Example 5 : Step (2)-c Methyl threo-3-[5-chloro-2-[3-[4-(4-methylphenyl) piperazin-1-yl]propyl]aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl)propionate (III T C) (753 mg, 1.29 mmol) is treated in a similar manner to that described in Example 3 to obtain carboxylic acid intermediate (IV T C) (707 mg, yield = 96.2%) in an amorphous form. IRνmax(CHCl 3 ) (cm -1 ):3348,1713 NMR(CDCl 3 )δ:2.07(3H,S),2.27(2H,m),2.80-3.72(12H,m), 3.78(3H,S),4.36(2H,m),6.17(3H),6.44(1H,d,J=8.6),6.76-7.42 (10H,m). Example 6 : Step (2)-d Methyl threo-3-[5-chloro-2-[3-(4-benzhydryl)piperazin-1-yl]propyl]aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl) propionate (III T d + III E d, threo/erythro = 4.71/1) (3.73 mg, 5.65 mmol) is treated in a similar manner to that described in Example 3 to obtain carboxylic acid intermediate (IV T d + IV E d, threo/erythro = 4.75/1 (NMR)) (3.42 g, yield = 93.7%) in an amorphous form. Spectral data for IV T d: IRνmax(CHCl 3 ) (cm -1 ):3348,1712 NMR(CDCl 3 )δ:1.90-3.40(14H,m),3.79(3H,S),4.31(1H,S),4.35 (2H,S),6.15(3H),6.40(1H,d,J=8.8),6.81(2H,d,J=8.8),6.95(1H,d, J=2.6),7.03-7.50(13H,m). Example 7 : Step (2)-e Methyl threo-3-[5-chloro-2-[(2-dimethylamino)ethyl] aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl)propionate (III T e) (0.476 mg, 1.084 mmol) is treated in a similar manner to that described in Example 3 and the product is recrystallized from dichloromethane/methanol to obtain carboxylic acid intermediate (IV T e) (395 mg, yield = 85.7%) as colorless prism-shaped crystals. Melting point:206-208°C Specific rotation:[α] D 24 =+472.5°(c=0.502,Methanol) Elemental analysis:C 20 H 25 N 3 O 4 SCl·1/2H 2 O Calculated:C,56.05;H,5.97;N,6.54 Found:C,56.01;H,5.93;N,6.58 IRνmax(nujol) (cm -1 ):3260,2346,1609 NMR(DMSO-d 6 )δ:2.79(6H,S),3.30(6H,m),3.75(3H,S),3.95(1H,d, J=1.2),4.09(1H,d,J=1.2),5.75(NH),6.69(1H,d,J=9.0),6.87(2H,d,J=8.8),6.88(1H,d,J=2.8),7.22(1H,d,d,J=2.8,9.0),7.30(2H,d,J =8.8). Reference example 3 Methyl erythro-3-[5-chloro-2-[(2-dimethylamino)ethyl] aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl)propionate (III E e) (439 mg, 1 mmol) is treated in a similar manner to that described in Example 3 and the product is recrystallized from methanol to obtain carboxylic acid (IV E e) (298 mg, yield = 70.1%) as colorless prism-shaped crystals. Melting point:162-164°C Specific rotation: [α] D 29 =-310.2(c=0.509,Methanol) Elemental analysis:C 20 H 25 N 2 O 4 SCl Calculated:C,56.53;H,5.93;N,6.59 Found:C,56.32;H,5.98;N,6.55 IRνmax(nujol)(cm -1 ):3342,1607 NMR(DMSO-d 6 )δ:2.50(6H,S),2.87(2H,m),3.31(2H,m),3.72(3H, S), 3.98(1H,d,J=5.4),4.20(1H,d,J=5.4),4.33(2H),5.96(NH),6.66 (1H,d,J=8.6),6.81(2H,d,J=9.0),7.11(1H,d,J=2.6),7.20(1H,d,d, J=2.6,8.6),7.23(2H,d,J=9.0). Step (3) in the process of the present invention is illustrated in the following Examples 8 ∼ 12. Example 8: Step (3)-a Threo-3-[5-chloro-2-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl) propionic acid (IV T a) (117 mg, 0.2 mmol) and pyridine (39 µl, 0.48 mmol) are dissolved in dichloromethane (4 ml) and a solution of acetyl chloride (17 µl, 0.24 mmol) in dichloromethane is added dropwise over 5 minutes under ice-cooling. The resulting reaction mixture is stirred under ice-cooling for 30 minutes, poured into ice, and then extracted with ethyl acetate. The layer of ethyl acetate is washed with a saturated saline solution, dried over magnesium sulfate and filtered. Threo-2-acetoxy intermediate (V T a) (118 mg, yield = 94.4%) is obtained in an amorphous form from the filtrate. HPLC:Column, TSKgel ODS 120T 4.6x250mm Mobile phase:acetonitrile/PICB-7 aqueous solution (60/40) Flow rate:1.0ml/min Detection:UV254nm Retention time:6.6min IRνmax(CHCl 3 )(cm -1 ):3340,2392,1736,1608 NMR(CDCl 3 )δ:2.20(3H,S),2.22(2H,m),2.70-3.60(12H,m),3.73 (2H),3.80(3H,S),3.87(3H,S),4.49(1H,d,J=2.0),5.31(1H,d, J=2.0),6.45(1H,d,J=8.6),6 76-7.15(8H,m),7.33(2H,d,J=8.6). Reference example 4 Erythro-3-[5-chloro-2-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl) propionic acid (IV E a) (625 mg, 1.066 mmol) and pyridine (0.21 ml, 2.6 mmol) are added to dichloromethane (2.5 ml), and 1N solution of acetyl chloride in dichloromethane (1.28 ml) is added dropwise over 5 minutes. The resulting reaction mixture is stirred under ice-cooling for 30 minutes, poured into ice water and extracted with ethyl acetate. The organic layer is washed with saline saturated solution and dried over MgSO 4 to obtain 2-acetoxy compound (V E a) (662 mg, yield = 98.8%) in an amorphous form from the filtrate. HPLC:Column, COSMOSIL 5 C18. Retention time:3.7min (V E a) IRνmax(CHCl 3 )(cm -1 ):3348,1734 NMR(CDCl 3 )δ:2.03(2H,m),1.98(3H,S),2.85-3.50(12H,m),3.68 (3H,S),3.84(3H,S),4.40(1H,d,J=8.8),5.35(1H,d,J=8.8),6.43(1H ,d, J=8.6),6.74(2H,d,J=8.6),6.81-7.20(8H,m),7.50(2H). Example 9: Step (3)-b 3-[5-Chloro-2-[3-(4-phenylpiperazin-1-yl)propyl] aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl) propionic acid (IV T b + IV E b, threo/erythro = 8.1/1) (1.945 g, 3.497 mmol) is acetylated in a similar manner to that described in Example 8 to obtain 2-acetoxy intermediate (V T b + V E b, threo/erythro = 8.62/1 (NMR)) (2.006 g, yield = 95.9%) in an amorphous form. Spectral data for V T b: IRνmax(CHCl 3 )(cm -1 ):3346,1736 NMR(CDCl 3 )δ:2.21(2H,m),2.19(3H,S),2.98-3.64(12H,m),3.79 (3H,S),4.47(1H,d,J=2.0),5.15(2H),5.29(2H,d,J=2.0),6.45(1H,d , J=8.6),6.77-7.38(11H,m). Example 10: Step (3)-c Threo-3-[5-chloro-2-[3-[4-(4-methylphenyl)piperazin-1-yl]propyl]aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl) propionic acid (IV T c) (707 mg, 1.24 mmol) is acetylated in a similar manner to that described in Example 8 to obtain 2-acetoxy intermediate (V T c) (722 mg, yield = 95.1%) in an amorphous form. IRνmax(CHCl 3 )(cm -1 ):3340,1737 NMR(CDCl 3 )δ:2.18(2H,m),2.19(3H,S),2.28(3H,S),2.98-3.60 (12H,m),3.79(3H,S),4.48(1H,d,J=2.2),5.29(1H,d,J=2.2),6.45 (1H,d,J=8.6),6.74-7.37(10H,m),8.10(2H). Example 11: Step (3)-d 3-[5-Chloro-2-[3-(4-benzhydrylpiperazin-1-yl)propyl] aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl) propionic acid (IV T d + IV E d, threo/erythro = 4.75/1) (3.423 g, 5.297 mmol) is acetylated in a similar manner to that described in Example 8 to obtain 2-acetoxy intermediate (V T d + V E d, threo/erythro = 4.75/1 (NMR)) (3.352 g, yield = 91.9%) in an amorphous form. Spectral data for V T d: IRνmax(CHCl 3 ) (cm -1 ):3342,1735 NMR:(CDCl 3 )δ:2.1(2H,m),2.19(3H,S),2.34-3.37(12H,m),3.79 (3H,S),4.32(1H,S),4.47(1H,d,J=2.0),5.30(1H,d,J=2.0),6.25(2H), 6.41(1H,d,J=8.6),6.75-7.46(16H,m). Example 12 : Step (3)-e Threo-3-[5-chloro-2-[2-(dimethylamino)ethyl]aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl) propionic acid (IV T e) (355 mg, 0.835 mmol) is acetylated in a similar manner to that described in Example 8 to obtain 2-acetoxy intermediate (V T e) (386 mg, yield = 99.0%) in an amorphous form. IRνmax(CHCl 3 ) (cm -1 ):3352,2426,1735,1609 NMR(CDCl 3 )δ:2.21(3H,S),2.82(6H,S),3.35(4H,m),3.82(3H,S) 4.26(1H,d,J=2.0),5.22(1H,d,J=2.0),5.77(2H),6.46(1H,d, J=8.6)6.85(2H,d,J=9.0),7.08(1H,d,J=2.4),7.15(1H,d,d,J=2.4, 8.6),7.32(2H,d,J=9.0). Reference example 5 Erythro-3-[5-chloro-2-[2-(dimethylamino)ethyl] aminophenylthio]-2-hydroxy-3-(4-methoxyphenyl) propionic acid (IV E e) (233 mg, 0.548 mmol) is acetylated in a similar manner to that described in Example 8 to obtain 2-acetoxy intermediate (V E e) (232 mg, yield = 90.6%) in an amorphous form. IRνmax(CHCl 3 ) (cm -1 ):3322,2394,1611 NMR(CDCl 3 )δ:1.85(3H,S),2.82(6H,S),3.39(4H,m),3.80(3H,S), 4.12(1H,d,J=10.8),5.24(1H,d,J=10.8),6.02(2H),6.44(1H,d, J=8.6),6.81(2H,d,J=8.8),6.94(1H,d,J=2.6),7.07(2H,d,J=8.8), 7.13(1H,d,d,J=2.6,8.6). Step (4) in the process of the present invention is illustrated in the following Examples 13 ∼ 17. Example 13 : Step (4)-a A solution of threo-2-acetoxy-3-[5-chloro-2-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]aminophenylthio]-3-(4-methoxyphenyl) propionic acid (V T a) (117 mg, 0.2 mmol) and pyridine (39 µl, 0.482 mmol) in dichloromethane (4 ml) is cooled to -30°C and a solution of phosphorus oxychloride (121 µl, 0.225 mmol) in dichloromethane (4 ml) is added dropwise over 5 minutes. The resulting reaction mixture is stirred under ice-cooling for 1 hour, poured into ice water and extracted with ethyl acetate. The layer of ethyl acetate is washed with an aqueous solution of NaHCO 3 and a saturated saline solution and dried over MgSO 4 . The resulting crude product (109 mg) is recrystallized from ethyl acetate/hexane to obtain(+)-cis-3-acetoxy-8-chloro-2,3-dihydro-2-(4-methoxyphenyl)-5-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl-1,5-benzothiazepine-4(5H)-one (cis-VIa) (87 mg, yield = 75.7%) as colorless prism-shaped crystals. The purity of compound (cis-VIa) was determined by HPLC under the following conditions. Column:COSMOSIL 5 C18 4.6x250mm Mobile phase:acetonitrile/PICB-7 aqueous solution(50/50) Flow rate:1.0ml/min Detection:UV254nm Retention time:11.0min The optical purity of compound (cis-VIa) was determined by HPLC using a column for resolving optical isomers under the following conditions. Column:CHIRALCEL OD 4.6x250mm Mobile phase:Hexane/Ethanol(90/10) Flow rate:1.0ml/min Detection:UV246nm Retention time:13.6min The physicochemical values and spectral data of compound (cis-VIa) are shown below. Melting point:109-111°C Optical rotation:+107.6°(c=1.018,Methanol) Elemental analysis:C 32 H 36 N 3 O 5 SCl Calculated:C,62.99;H,5.95;N,6.89 Found:C,63.02;H,6.03;N,6.96 IRνmax(CHCl 3 ) (cm -1 ):3340,2392,1736,1608 NMR(CDCl 3 )δ:2.22(2H,m),2.20(3H,S),2.70-3.60(12H,m),3.73 (2H),3.80(3H,S),3.87(3H,S),4.49(1H,d,J=2.0),5.31(1H,d, J=2.0),6.45(1H,d,J=8.6),6.76-7.15(8H,m),7.33(2H,d,J=8.6) Compound (cis-VIa) (3.5 g, 5.736 mmol) and citric acid (1.205 g, 5.737 mmol) are dissolved in ethanol (30 ml) to obtain the citrate (4.366 g, yield = 94.9%) as colorless prism-shaped crystals. Melting point:179-182°C Specific rotation:[α] D 23 =+65.0±1.0(c=1.007,Methanol) Elemental analysis:C 32 H 36 N 3 O 5 SCl·C 6 H 8 O 7 Calculated:C,56.88;H,5.52;N,5.23 Found:C,56.75;H,5.54;N,5.35 IRνmax(nujol) (cm -1 ):3430,2620,1737,1674 NMR(DMSO-d 6 )δ:1.79(2H,m),1.84(3H,S),2.56-3.82,4.20-4.32 (17H,m),3.76(3H,S),3.78(3H,S),5.04(1H,d,J=8.2),5.21(1H,d, J=8.2),6.80-7.86(11H,m),10.78(3H ). Reference example 6 A solution of erythro-2-acetoxy-3-[5-chloro-2-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]aminophenylthio]-3-(4-methoxyphenyl) propionic acid (V E a) (2.189 mg, 3.484 mmol) and pyridine (1.44 ml, 17.804 mmol) in dichloromethane (16 ml) was cooled to -30°C and 1N solution of phosphorus oxychloride in dichloromethane (4.27 ml) was added over 10 minutes. The resulting reaction mixture was stirred under ice-cooling for 1 hour, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium bicarbonate and a saturated saline solution, and dried over MgSO 4 to obtain the crude product (2.036 g), which was converted to its oxalate. The oxalate was recrystallized from ethanol to obtain the oxalate (2.127 g, yield = 87.1%, m.p. 155 ∼ 158°C) as pale yellow prism-shaped crystals. Subsequently the oxalate (1.312 g) was neutralized with an aqueous solution of bicarbonate and extracted with ethyl acetate. The organic layer was dried over MgSO 4 and free-base compound (trans-VIa) (1.138 g, yield = 99.6%) was obtained. Compound (trans-VIa) (1.138 g) was treated with citric acid (392 mg, 1.865 mmol) to give a citrate. The resulting citrate was recrystallized from methanol to obtain (+)-trans-3-acetoxy-8-chloro-2,3-dihydro-2-(4-methoxyphenyl)-5-[3-[4-(2-methoxyphenyl)piperazin-1-yl] propyl-1,5-benzothiazepine-4(5H)-one citrate (1.432 g, yield = 95.4%) as colorless prism-shaped crystals. Melting point:191-192°C Specific rotation: [α] D 23 =+275.8° (c=1.006,Methanol) Elemental analysis:C 32 H 36 N 3 O 5 SCl•C 6 H 8 O 7 Calculated:C,56.88;H,5.52;N,5.23 Found:C,57.02;H,5.63;N,5.46 IRνmax(nujol) (cm -1 ):3446,2542,1736,1640 NMR(DMSO-d 6 )δ:1.75(2H,m),1.87(3H,S),2.55-3.68,4.05-4.33 (16H,m),2.61(2H,S),2.65(2H,S),3.74(3H,S),3.77(3H,S),4.86 (1H,d,J=11.0),4.99(1H,d,J=11.0),6.80-7.86(11H,m). Example 14: Stet (4)-b 2-Acetoxy-3-[5-chloro-2-[3-(4-phenylpiperazin-1-yl) propyl]aminophenylthio]-3-(4-methoxyphenyl) propionic acid (V T b + V E b, threo/erythro = 8.61/1) (2.006 g, 3.353 mmol) is subjected to a ring closure reaction in a similar manner to that described in Example 13 to obtain crude product (cis-VIb + trans-VIb) (1.941 g). This crude product is converted to its oxalate, which is recrystallized to obtain oxalate of (+)-cis-3-acetoxy-8-chloro-2,3-dihydro-2-(4-methoxyphenyl)-5-[3-phenylpiperazin-1-yl]propyl-1,5-benzothiazepine-4(5H)-one (cis-VIb) (1.298 g, yield = 48.4%) as colorless prism-shaped crystals. Melting point:185-188°C Specific rotation: [α] D 23 =+74.2° (c=1.005,Methanol) Elemental analysis:C 31 H 34 N 3 O 4 SCl•C 2 H 2 O 4 Calculated:C,59.14;H,5.41;N,6.27 Found:C,58.92;H,5.51;N,6.42 IRνmax(nujol)(cm -1 ):3482,3352,2594,1758,1688 NMR(DMSO-d 6 )δ:1.85(2H,m),1.84(3H,S),2.75-3.75,4.18-4.42 (12H,m),3.78(3H,S),5.04(1H,d,J=7.4),5.20(1H,d,J=7.4),5.62 (2H),6.75-7.87(12H,m). Example 15: Step (4)-c Threo-2-acetoxy-3-[5-chloro-2-[3-[4-(4-methylphenyl) piperazin-1-yl]propyl]aminophenylthio]-3-(4-methoxyphenyl) propionic acid (V T c) (722 mg, 1.179 mmol) is subjected to a ring closure reaction in a similar manner to that described in Example 13 to obtain crude product (711 mg). This product is recrystallized from ethyl acetate/hexane to obtain (+)-cis-3-acetoxy-8-chloro-2,3-dihydro-2-(4-methoxyphenyl)-5-[3-[4-(4-methylphenyl)piperazin-1-yl]propyl]-1,5-benzothiazepine-4(5H)-one (cis-VIc) (588 mg, yield = 84.0%) as colorless prism-shaped crystals. Melting point:118-120°C Specific rotation:[α] D 24 =+109.0°(c=1.008,Methanol) Elemental analysis:C 32 H 36 N 3 O 4 SCl Calculated:C,64.69;H,6.11;N,7.07 Found:C,64.47;H,6.13;N,7.06 IRνmax(nujol) (cm -1 ):1746,1678 NMR(CDCl 3 )δ:1.83(2H,m),1.91(3H,S),2.26(3H,S),2.54(6H,m), 3.1(4H,m),3.63(1H,m),4.49(1H,m),3.82(3H,S),5.03(1H,d,J=7.6) , 5.15(1H,d,J=7.6),6.78-7.55(11H,m). Example 16 : Step (4)-d 2-Acetoxy-3-[5-chloro-2-[3-(4-benzhydrylpiperazin-1-yl) propyl]aminophenylthio]-3-(4-methoxyphenyl) propionic acid (V T d + V E d, threo/erythro = 4.75/1) (3.352 g, 4.87 mmol) is subjected to a ring closure reaction in a similar manner to that described in Example 13 to obtain crude product (cis-VId + trans-VId) (3.196 g, yield = 90.0%). The crude product is subjected to column chromatography on silica gel. The eluate eluted with ethyl acetate is converted to its hydrochloride. The hydrochloride is washed with ethyl ether to obtain hydrochloride of(+)-cis-3-acetoxy-8-chloro-2,3-dihydro-5-[3-(4-benzhydrylpiperazin-1-yl]propyl-2-(4-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one (cis-VId) (2.1 g, yield = 57.8%) in an pale yellow colored amorphous form. Specific rotation: [α] D 26 =+64.2°(c=1.005,Methanol) Elemental analysis:C 38 H 40 N 3 O 4 SCl·1.8HCl·1/2H 2 O Calculated:C,61.26;H,5.82;N,5.64 Found:C,60.95;H,5.91;N,5.59 IRνmax(CHCl 3 ) (cm -1 ):3410,2392,1676 NMR(CDCl 3 )δ:1.88(3H,S),2.26(2H,m),3.13-4.99(13H,m),3.82 (3H,S),5.0(1H,d,J=7.8),5.08(1H,d,J=7.8),6.77-8.10(17H,m),13 .04 (1H),13.71(1H). Example 17 : Step (4)-e Threo-2-acetoxy-3-[5-chloro-2-[(2-dimethylamino)ethyl] aminophenylthio]-3-(4-methoxyphenyl) propionic acid (V T e) (390 mg, 0.835 mmol) is subjected to a ring closure reaction in a similar manner to that described in Example 13 to obtain crude product (363 mg). The crude product is converted to maleate, which is recrystallized from ethanol to obtain maleate of (+)-cis-3-acetoxy-8-chloro-2,3-dihydro-5-[2-(2-dimethylamino) ethyl]-2-(4-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one (cis-VIe) (368 mg, yield = 78.0%) as colorless needle-shaped crystals. Melting point:159-160°C Specific rotation: [α] D 25 =+75.1°(c=1.006,Methanol) Elemental analysis:C 22 H 25 N 2 O 4 SCl·C 4 H 4 O 4 Calculated:C,55.27;H,5.17;N,4.96 Found:C,55.40;H,5.29;N,5.00 IRνmax(nujol) (cm -1 ):2616,2410,1752,1684 NMR(CDCl 3 )δ:1.92(3H,S),2.90(6H,S),3.37(2H,m),3.83(3H,S), 4.33(2H,m),5.03(1H,d,J=7.8),5.10(1H,d,J=7.8),6.27(2H,S), 6.91(2H,d,J=9.0),7.36(2H,d,J=9.0),7.41(1H,d,J=8.6),7.56(1H, d,d,J=2.4,8.6),7.74(1H,d,J=2.4). Reference example 7 Erythro-2-acetoxy-3-[5-chloro-2-[(2-dimethylamino)ethyl] aminophenylthio]-3-(4-methoxyphenyl) propionic acid (V E e) (232 mg, 0.5 mmol) was subjected to a ring closure reaction in a similar manner to that described in Example 13 to obtain crude product (206 mg). The crude product was converted to maleate, which is recrystallized from ethanol maleate of (+)-trans-3-acetoxy-8-chloro-2,3-dihydro-5-[2-(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one (trans-VIe) (155 mg, yield = 59.4%) as colorless needle-shaped crystals. Melting point:151-152°C Specific rotation:[α] D 25 =+391.5°(c=1.016,Methanol) Elemental analysis:C 22 H 25 N 2 O 4 SCl·C 4 H 4 O 4 Calculated:C,55.22;H,5.20;N,4.96 Found:C,54.93;H,5.28;N,4.95 IRνmax(nujol) (cm -1 ):3578,3500,2660,1738,1692 NMR(CDCl 3 )δ:1.95(3H,S),2.88(6H,S),3.32(2H,m),3.80(3H,S), 4.29(2H,m),4.53(1H,d,J=11.0),5.01(1H,d,J=11.0),6.27(2H,S), 6.85(2H,d,J=8.6),7.02(2H,d,J=8.6),7.55(3H,m). The syntheses of starting compounds (Ia ∼ e) for the process of the present invention based on the above Reaction scheme 4 are shown in the following reference examples 8 ∼ 18. Reference example 8 : 6-chloro-3-(3-chloropropyl)-2-benzothiazolone (X) A solution of 6-chloro-benzothiazolone (VIII) (55.7 g, 0.3 mol), K 2 CO 3 (62.1 g, 0.45 mol) and 1-bromo-3-chloropropane (IX) (71 g, 0.45 mol) in acetone (600 ml) was refluxed for 16 hours. After cooling, the inorganic substance was filtered off and washed dichloromethane. The filtrate and washings were combined and evaporated in vacuo. The residue was washed with hexane and recrystallized from dichloromethane to obtain compound (X) (73.5 g, yield = 93.4%) as colorless needle-shaped crystals. Melting point:131-132°C Elemental analysis:C 10 H 9 NOSCl 2 Calculated:C,45.82;H,3.46;N,5.34 Found:C,45.56;H,3.50;N,5.41 IRνmax(nujol) (cm -1 ):1673,1162 NMR(CDCl 3 )δ:2.21(2H,quint,J=6.2),3.61(2H,t,J=6.2),4.11 (2H,t,J=7.0),7.08(1H,d,J=8.6),7.32(1H,d,d,J=8.6,2.0),7.43 (1H,d,J=2.0). Reference example 9 : 6-chloro-3-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]-2-benzothiazolone (XIIa) A solution of compound (X) (73.4 g, 0.28 mol), K 2 CO 3 (85.2 g, 0.62 mol), 1-(2-methoxyphenyl)piperazine hydrochloride (XIa) (70.44 g, 0.31 mol), and KI (46.7 g, 0.28 mol) in DMF (500 ml) was stirred at 110°C for 2 hours. After cooling, inorganic substance was filtered off and washed with ethyl acetate. The filtrate and washings were combined and evaporated in vacuo. The residue was recrystallized from EtOH (400 ml). The crystals were filtered off, washed with water and ethanol and recrystallized from ethanol to obtain compound (XIIa) (107.8 g, yield = 92%) as colorless needle-shaped crystals. Melting point:120-121°C Elemental analysis:C 21 H 24 N 3 O 2 SCl Calculated:C,60.35;H,5.79;N,10.06 Found:C,60.39;H,5.77;N,10.19 IRνmax(nujol) (cm -1 ):1684,1183 NMR(CDCl 3 )δ:1.97(2H,quint,J=6.8),2.48(2H,t,J=6.8),2.63 (4H,m),3.08(4H,m),3.86(3H,S),4.04(2H,t,J=6.8),6.95(4H,m),7. 16 (1H,d,J=8.8),7.28(1H,d,d,J=8.8,2.2),7.42(1H,d,J=2.2). Reference example 10 : 6-chloro-3-[3-(4-phenylpiperazin-1-yl)propyl]-2-benzothiazolone (XIIb) A solution of compound (X) (3.71 g, 20 mmol), K 2 CO 3 (3.31 g, 24 mol), phenylpiperazine (XIb) (3.24 g, 20 mmol), and KI (3.98 g, 24 mmol) in DMF (20 ml) was stirred at 100°C for 5 hours and concentrated in vacuo. The residue was extracted with dichloromethane, washed with a saturated saline solution and dried over MgSO 4 . The dichloromethane layer was subjected to column chromatography on silica gel. The eluate eluted with dichloromethane/ethyl acetate (4/1) was recrystallized from ethyl ether to obtain compound (XIIb) (4.8 g, yield = 61.9%) as colorless prism-shaped crystals. Melting point:126-127°C Elemental analysis:C 20 H 22 N 3 OSCl Calculated:C,61.93;H,5.72;N,10.83 Found:C,61.83;H,5.78;N,10.90 IRνmax(nujol) (cm -1 ):1680,1177 NMR(CDCl 3 )δ:1.97(2H,quint,J=6.8),2.46(2H,t,J=6.8),2.58 (4H,m),3.19(4H,m),4.04(2H,t,J=6.8),6.88(3H,m),7.13(1H,d, J=8.6), 7.28(3H,m),7.41(1H,d,J=2.0). Reference example 11 : 6-chloro-3-[3-(4-methylphenyl) piperazin-1-yl]propyl]-2-benzothiazolone (XIIc) A solution of compound (X) (3.71 g, 20 mmol), K 2 CO 3 (4.97 g, 36 mol), 4-(4-methylphenyl)piperazine hydrochloride (XIc) (5.98 g, 24 mmol), and KI (3.98 g, 24 mmol) in DMF (20 ml) was stirred at 100°C for 5 hours, concentrated in vacuo and filtered. The resulting crystals were washed with water and recrystallized from isopropyl ether to obtain compound (XIIc) (5.1 g, yield = 63.7%) as colorless needle-shaped crystals. Melting point:125-126°C Elemental analysis:C 21 H 24 N 3 OSCl Calculated:C,62.76;H,6.02;N,10.46 Found:C,62.54;H,6.05;N,10.63 IRνmax(nujol) (cm -1 ):1681,1185 NMR(CDCl 3 )δ:1.95(2H,quint,J=6.8),2.27(3H,S),2.45(2H,t, J=6.8),2.57(4H,m),3.13(4H,m),4.03(2H,t,J=7.0),6.84(2H,d, J=8.6),7.08(2H,d,J=8.6),7.13(1H,d,J=8.6),7.27(1H,d,d,J=8.6, 2.0),7.41(1H,d,J=2.0) Reference example 12 : 6-chloro-3-[3-(4-benzhydrylpiperazin-1-yl]propyl]-2-benzothiazolone (XIId) A solution of compound (X) (3.71 g, 20 mmol), K 2 CO 3 (3.31 g, 24 mmol), 4-benzhydrylpiperazine (XId) (6.06 g, 24 mmol), and KI (3.98 g, 24 mmol) in DMF (20 ml) was stirred at 100°C for 5 hours, concentrated in vacuo and extracted with dichloromethane. The resulting dichloromethane layer was dried over MgSO 4 , and subjected to column chromatography on silica gel. The eluate eluted with dichloromethane/ethyl acetate (10/1) was recrystallized from ether to obtain compound (XIId) (5.9 g, yield = 61.7%) as colorless prism-shaped crystals. Melting point:130-132°C Elemental analysis:C 27 H 28 N 3 OSCl Calculated:C,67.84;H,5.90;N,8.79 Found:C,67.75;H,6.04;N,8.92 IRνmax(nujol) (cm -1 ):1678,1160 NMR(CDCl 3 )δ:1.88(2H,quint,J=6.8),2.37(2H,t,J=6.8),2.40 (8H,m),3.97(2H,t,J=6.8),4.22(1H,S),7.1(1H,d,J=8.6),7.25 (11H,m),7.42(1H,d,J=1.8). Reference example 13 : 6-chloro-3-[2-(dimethylamino) ethyl]-2-benzothiazolone (XIIe) A solution of compound (VIII) (9.28 g, 50 mmol), N,N-dimethylaminoethylchloride hydrochloride (XIe) (7.92 g, 55 mmol), and K 2 CO 3 (16.58 g, 120 mmol) in acetone (93 ml) was refluxed for 20 hours with stirring. After the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was extracted with ethyl acetate. The layer of ethyl acetate was dried over MgSO 4 and subjected to column chromatography on silica gel. From the eluate eluted with ethyl acetate, compound (XIIe) (3.3 g, yield = 64.3%) was obtained as an oil. IRνmax(nujol) (cm -1 ):1680,1168 NMR(CDCl 3 )δ:2.31(6H,S),2.59(2H,t,J=7.2),4.03(2H,t,J=7.2), 7.01(1H,d,J=8.6),7.29(1H,d,d,J=8.6,2.2),7.41(1H,d,J=2.2). Reference example 14 : 5-chloro-2-[3-[4-(2-(methoxyphenyl)piperazin-1-yl]propyl]-aminobenzenethiol (Ia) To a solution of compound (XIIa) (12.54 g, 30 mmol) in ethanol (76 ml) was added a solution of KOH (8.42 g, 150 mmol) in water (8.4 ml). The mixture was refluxed in a stream of nitrogen for 4 hours. The ethanol was distilled away in vacuo. The residue was cooled and ice water (70 g) was added. The resulting liquid was neutralized to pH 4.49 with an excess of acetic acid (30 ml). The precipitated crystals were filtered off, washed with water until the smell of acetic acid completely disappeared, and then washed with methanol (20 ml) and ether (30 ml), and dried in vacuo overnight to obtain pale yellow powder like crystals (Ia) (10.95 g, yield 91.9%). Purity:96.0%(HPLC) Melting point:137-142°C Elemental analysis:C 20 H 26 N 3 OSCl Calculated:C,61.22;H,6.63;N,10.71 Found:C,60.93;H,6.73;N,10.67 IRνmax(nujol) (cm -1 ):3246,2522 NMR(CDCl 3 )δ:1.91(2H,t,J=6.4),2.59(2H,t,J=6.4)2.73,3.14 (8H,m),2.95(NH,SH),3.24(2H,t,J=6.4),3.87(3H,S),6.5-7.37(7H, m). HPLC condition: Column:COSMOSIL 5 C18 4.6x150mm Mobile phase:acetonitrile/PICB-7 aqueous solution(50/50) Flow rate:1.0ml/min Detection:UV254nm Retention time:6.2min Reference example 15 : 5-chloro-2-[3-(4-phenylpiperazin-1-yl)propyl]aminobenzenethiol (Ib) Compound (XIIb) (1.94 g, 5 mmol) was treated in a similar manner to that described in Reference example 14 to obtain pale yellow powder-like crystals (Ib) (1.746 g, yield = 96.5%). Purity:93.6%(HPLC) Melting point:135-145°C Elemental analysis:C 19 H 24 N 3 SCl Calculated:C,62.78;H,6.63;N,11.60 Found:C,62.35;H,6.71;N,11.47 IRνmax(nujol) (cm -1 ):3250,2150 NMR(CDCl 3 )δ:1.98(2H,quint,J=6.6),2.10(NH,SH),2.67(2H,t, J=6.6),2.77(4H,m),3.15-3.40(6H,m),6.56(1H,d,J=9.0),6.83-7.4 0 (7H,m). Reference example 16: 5-chloro-2-[3-[4-(4-methylphenyl)piperazin-1-yl]propyl]aminobenzenethiol (Ic) Compound (XIIc) (2.128 g, 5.294 mmol) was treated in a similar manner to that described in Reference example 14 to obtain pale yellow powder-like crystals (Ic) (1.872 g, yield = 94.1%). Purity:96.3%(HPLC) Melting point:137-147°C Elemental analysis:C 20 H 26 N 3 SCl•1/2H 2 O Calculated:C,62.43;H,7.01;N,10.91 Found:C,62.84;H,6.81;N,11.00 IRνmax(nujol) (cm -1 ):3362,2318 NMR(CDCl 3 )δ:1.97(2H,quint,J=6.6),2.28(3H,S),2.45(NH,SH),2.45(NH,SH), 2.66(2H,t,J=6.6),2.77(4H,m),3.11-3.34(6H,m),6.53(1H,d,J=8.6 ), 6.80-7.37(6H,m). Reference example 17: 5-chloro-2-[3-(4-benzhydryl piperazin-1-yl)propyl]-aminobenzenethiol (Id) Compound (XIId) (2.87 g, 6.004 mmol) was treated in a similar manner to that described in Reference example 14 to obtain pale yellow powder-like crystals (Id) (2.584 g, yield = 95.2%). Purity:90.7%(HPLC) Melting point:142-150°C IRνmax(nujol) (cm -1 ):3260,2336 NMR(CDCl 3 )δ:1.84(2H,t,J=6.2),2.15(NH,SH),2.35-2.65(8H,m), 2.52(2H,t,J=6.2),3.18(2H,t,J=6.2),4.25(1H,S),6.49(1H,d, J=9.0),7.05-7.47(12H,m). Reference example 18: 5-chloro-2-[2-(dimethylamino) ethyl]aminobenzenethiol (Ie) Compound (XIIe) (3.825 g, 14.898 mmol) was treated in a similar manner to that described in Reference example 14 to obtain pale yellow powder-like crystals (Ie) (1.617 g, yield = 47.0%). Purity:92.7%(HPLC) Melting point:135-140°C Elemental analysis:C 10 H 15 N 2 SCl Calculated:C,52.05;H,6.55;N,12.14 Found:C,51.73;H,6.52;N,12.23 IRνmax(nujol) (cm -1 ):3230,2156 NMR (CDCl 3 )δ:2.32(6H,S),2.63(2H,t,J=6.0),3.21(2H,t,J=6.0), 3.26(NH,SH),6.53((1H,d,J=8.6),7.11(1H,d,d,,J=2.6,8.6),7.37 (1H,d,J=2.6). The present invention includes preparing a 1,5-benzothiazepine derivative of formula (VI) by a process as described above and formulating said derivative in to the required composition with a diluent excipient or carrier.

Claims: A process for stereoselectively preparing a threo-form of a compound represented by formula (III): wherein Y represents hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, or phenyl or naphthyl which may be optionally substituted; n is an integer of 1 to 6; R 1 represents an amino group represented by the formula: -NR 1a R 1b wherein R 1a and R 1b each independently represents hydrogen, straight or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or phenyl or naphthyl which may be substituted, or R 1a and R 1b may form, taken together with the nitrogen to which R 1a and R 1b are attached, a cyclic amino group which may be substituted, provided that said cyclic amino group may further contain one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur in the cyclic skeleton; and R 2 represents C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, said process comprising reacting an o-(aminoalkylamino)thiophenol compound represented by formula (I): wherein Y, n and R 1 are as defined above with an ester of trans-3-(4-methoxyphenyl)glycidic acid represented by formula (II): wherein R 2 is as defined above, at an elevated temperature in a nonpolar solvent in the presence of a divalent or trivalent iron ion. A process for stereoselectively preparing a cis-form of 1,5-benzothiazepine derivative represented by formula (VI): wherein Y, n and R 1 are as defined in claim 1, the processing comprising: (1) stereoselectively preparing a threo-form of a compound represented by formula (III) by the process defined in claim 1, (2) hydrolysing the ester group of the compound obtained in Step (1) to yield a carboxylic acid represented by formula (IV): (3) acetylating the 2-hydroxyl group of the carboxylic acid obtained in Step (2) to convert it into a 2-acetoxy compound represented by formula (V): and (4) subjecting the 2-acetoxy compound obtained in Step (3) to a ring closure reaction to convert it into a 1,5-benzothiazepine derivative represented by formula (VI). A process as claimed in claim 1 or 2 wherein said nonpolar solvent is xylene. A process as claimed in claim 1, claim 2 or claim 3, wherein said trivalent iron ion is that derived from iron (III) hydroxide oxide. A process for preparing a pharmaceutical composition having vasodilation action or cardiac-muscle protecting action, which process comprises preparing a 1,5-benzothiazepine derivative of formula (VI) by the process claimed in claim 2, claim 3, or claim 4 and thereafter formulating said derivative in to the required composition with a diluent excipient or carrier.

Inventors: HARADA HIROSHI, OOSUGI EIICHI, SAKAI KATSUNORI, YAMAMORI TERUO, HARADA, HIROSHI, OOSUGI, EIICHI, SAKAI, KATSUNORI, YAMAMORI, TERUO
Applicants: SHIONOGI & CO, SHIONOGI & CO., LTD.
Application year: 1994
Main classification: C07C323
IPC codes: C07C323, C07D281, C07D295, C07C319